INTRODUCTION — Surgical resection of abnormal parathyroid glands is the only curative treatment for primary hyperparathyroidism [1,2]. Abnormal parathyroid glands can be removed via bilateral neck exploration or focused parathyroidectomy.

The bilateral neck exploration approach relies on visual inspection of all parathyroid glands to ensure that all abnormal ones are removed [3,4]. The focused approach, however, does not require exposure of all glands. Thus, a focused parathyroidectomy requires nonvisual confirmation that all abnormal glands have been removed in order to prevent higher failure rates.

Intraoperative parathyroid hormone (PTH) monitoring leverages the short half-life of the PTH hormone (three to five minutes) to provide the necessary assurance that a focused parathyroidectomy has been adequately performed (ie, all hypersecreting glands have been removed) before concluding the surgery [5-8]. In addition, intraoperative PTH measurements accurately predict postoperative calcium levels [7,9-17].

The use of intraoperative PTH monitoring in patients with sporadic primary hyperparathyroidism will be reviewed here. Parathyroid surgery techniques, preoperative localization of parathyroid glands, and the medical management of hyperparathyroidism are discussed elsewhere. (See "Parathyroid exploration for primary hyperparathyroidism" and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism" and "Primary hyperparathyroidism: Management".)

INTRAOPERATIVE PTH ASSAY — Parathyroid hormone (PTH) assays measure circulating levels of PTH. Because the half-life of the parathyroid hormone is very short (three to five minutes), the PTH level becomes a reliable surrogate for in vivo parathyroid function. (See "Parathyroid hormone assays and their clinical use".)

Intraoperative PTH monitoring utilizes one of the rapid immunochemiluminescence assays, which allows for repeated measurements of PTH levels while the patient is in the operating room [18-20]. The assays can be completed with a turnaround time of 8 to 20 minutes [21]. The intraoperative PTH assay should be performed in or close to the operating room to avoid delay caused by sample transport. Because of the large number of samples required to apply the intraoperative monitoring protocols, the facility is required to have a PTH assay with a fast turnaround time (<15 minutes).

To perform intraoperative PTH monitoring during parathyroid surgery, blood samples are collected at predetermined time intervals by the anesthetist (via an established peripheral venous or arterial line) or the surgeon (via a needle puncture of the internal jugular vein, anterior jugular vein, or external jugular vein in the operative field). For each sample, 3 to 5 mL of whole blood is collected in an ethylenediamine tetraacetic acid (EDTA) tube. It is important to avoid hemolysis during blood collection by filling the EDTA tube completely and avoiding any shaking of the sample [22,23]. Blood samples are then sent for PTH assay, the results of which are interpreted according to one of the intraoperative PTH monitoring protocols.

INTRAOPERATIVE PTH MONITORING PROTOCOLS — Intraoperative parathyroid hormone (PTH) monitoring protocols help guide the surgical decision-making process. When properly followed, an established intraoperative monitoring protocol can provide assurance that all hyperfunctioning parathyroid tissue has been adequately excised before the surgical procedure is concluded.

At each facility, surgeons should consistently use a protocol that is practical, specific, and reproducible under their local conditions. The goal is to cure 97 to 99 percent of patients of hyperparathyroidism.

Commonly used protocols — The most commonly used intraoperative PTH monitoring protocols include the ">50 percent PTH drop criterion" protocol and the dual criterion protocol (table 1).

>50 percent PTH drop criterion — The >50 percent PTH drop criterion protocol typically uses four intraoperative PTH samples (pre-skin-incision, pre-gland-excision, 5 minutes post-gland-excision, 10 minutes post-gland-excision) to construct a curve (figure 1) [24-28]. Some centers omit the pre-gland-excision and/or the 5-minute sample due to concerns of cost or proximity to the laboratory. The timing of the second (pre-gland-excision) sample is most critical as a collection made too early (during parathyroid gland dissection) or too late (after early disruption of the blood supply) could potentially miss the peak PTH level and lead to false negative results.

The >50 percent PTH drop criterion protocol sets a decrease in PTH values of >50 percent from the higher level of either the pre-skin-incision level or pre-gland-excision level as the criterion to conclude surgery. As an example, if the PTH value at 10 minutes post-gland-excision decreases >50 percent from the pre-skin-incision level, the procedure can be stopped without further neck exploration or visualization of the remaining parathyroid glands.

If the PTH value does not decrease by >50 percent at 10 minutes after gland excision, the surgeon can repeat the PTH level at 20 minutes. In most patients, the >50 percent PTH drop criterion is met with this additional measurement [25,29]. If the criterion is still not met after 20 minutes, surgery is continued by examining the other glands. The same protocol for blood sampling is repeated for each additional gland removed or, if all glands are abnormal, after all abnormal tissue has been removed.

In retrospective studies, the >50 percent PTH drop criterion predicted postoperative eucalcemia with an accuracy of 96 percent for at least six months [30,31].

Dual criteria protocol — Another widely used method for PTH monitoring, the dual criteria protocol, requires a minimum of two intraoperative samples (the pre-skin-incision sample and a post-gland-excision sample) (table 1) [9,32-35].

The first sample is obtained preincision after induction of anesthesia. The second blood sample is collected from the same site 10 minutes after excision of a suspected adenoma. If the second PTH value decreases >50 percent compared with the first sample and has returned to the normal range, the dual criteria are met, and surgery is concluded [11,14,32,36]. If the second sample does not meet one or both criteria, a third sample is drawn 20 minutes after gland excision. If the third sample again fails to meet the dual criteria, further exploration is conducted until all abnormal glands are identified and removed.

Fulfillment of the dual criteria also predicts postoperative eucalcemia with an accuracy of 97 percent, according to a retrospective study of 1882 patients undergoing parathyroidectomy for primary hyperparathyroidism [9].

Other protocols — Other protocols of intraoperative PTH monitoring have been proposed in which the timing of PTH sampling, the required magnitude of PTH decrease, or the required final PTH value is adjusted to make the protocol more or less stringent (table 1) [34,37,38].

More stringent protocol — The use of a more stringent protocol, such as requiring that the >50 percent decline in PTH occur at 5 minutes rather than 10 minutes postexcision, may decrease the number of operative failures but increase the incidence of unnecessary bilateral exploration [25]. In a series of 1882 patients who underwent parathyroidectomy using the >50 percent PTH drop criterion for primary hyperparathyroidism, 206 additional patients would have undergone unnecessary surgery if the criterion was required to be met at 5 rather than 10 minutes [9].

Another more stringent protocol requires that the intraoperative PTH fall by >50 percent and to a level below 40 pg/mL (which is below the upper limit of the normal range) [11,12,39]. This more stringent protocol, however, has not been evaluated prospectively but is associated with the lowest risk of persistence in retrospective studies [40].

Less stringent protocol — The use of a less stringent protocol minimizes unnecessary surgery but carries a higher risk of persistent hyperparathyroidism after surgery. As an example, some users of PTH monitoring accept any reduction as purportedly indicative of an adequate resection or omit altogether the use of PTH monitoring during unilateral surgery.

Technical and patient factors affecting all protocols — Technical and patient factors that can cause an insufficient decline in PTH levels include decreased renal clearance in patients with chronic renal insufficiency [41], baseline sample hemodilution or hemolysis (both decrease baseline PTH value) [23], a missed PTH peak (figure 1), and laboratory errors [21]. In addition, when the baseline PTH level is drawn from an internal jugular vein ipsilateral to a single adenoma, it can take longer for the PTH level to decrease adequately after the adenomatous gland is excised. (See "Parathyroidectomy in end-stage kidney disease", section on 'Resect abnormal glands with intraoperative PTH monitoring'.)

These factors can unnecessarily prolong operative and anesthesia time by mandating additional PTH testing and may also direct unnecessary excision of parathyroid glands. When these issues are suspected, a down-sloping postresection PTH curve can provide some assurance that the parathyroid surgery will predict cure and in fact is often used as a key finding in deciding when to conclude the surgery [42,43].

Technical factors such as postexcision sample dilution or hemolysis (both decrease PTH value) can lead to a falsely adequate drop in PTH, which in turn can lead to missed multiglandular disease and operative failure.

Renal or hereditary hyperparathyroidism — It should be noted that all intraoperative PTH monitoring protocols are intended for patients undergoing surgery for sporadic primary hyperparathyroidism. Thus, when intraoperative PTH monitoring is used in patients with secondary or hereditary hyperparathyroidism, the usual protocols do not necessarily apply [44]. Nevertheless, retrospective studies have shown that intraoperative PTH monitoring in patients with chronic renal insufficiency is reliable [17,45]. (See "Parathyroid surgery for inherited syndromes", section on 'Intraoperative PTH monitoring' and "Parathyroidectomy in end-stage kidney disease", section on 'Resect abnormal glands with intraoperative PTH monitoring'.)

Patients with multiple endocrine neoplasia (MEN) syndrome, parathyroid carcinoma, and familial hyperparathyroidism have a higher risk of persistent or recurrent hyperparathyroidism after surgery, even when intraoperative PTH monitoring indicates that the surgery is adequate [5-8,23,27,46,47].

OTHER USES OF RAPID PTH ASSAYS — Although intraoperative parathyroid hormone (PTH) assays are primarily used in focused parathyroidectomies to determine the adequacy of surgery as detailed above, such assays can also be used to lateralize hyperfunctioning parathyroid glands preoperatively, identify missing parathyroid glands, or confirm the presence of parathyroid tissue.

Lateralization of hyperfunctioning parathyroid gland — Bilateral jugular venous PTH sampling can be performed preoperatively or intraoperatively to lateralize hyperfunctioning parathyroid gland(s) to one side of the neck. In patients with otherwise negative preoperative localization studies, a positive bilateral jugular venous PTH sampling (defined as ≥10 percent difference in PTH measurements) can convert a bilateral to a unilateral neck exploration.

Blood samples are taken from both internal jugular veins, under ultrasound guidance (figure 2). Bilateral jugular venous sampling led to a successful unilateral neck exploration in 70 to 80 percent of patients when used in conjunction with intraoperative PTH monitoring [48,49]. (See 'Intraoperative PTH monitoring protocols' above.)

Missing glands — Bilateral jugular venous sampling for PTH levels can also be performed at the time of neck exploration to localize a missing gland, especially during a difficult exploration. A unilateral elevation of PTH leads the surgeon to explore the ipsilateral side of the neck for a missing hyperfunctioning gland. Similar readings on both sides of the neck in the context of a missing gland may suggest the presence of hyperfunctioning parathyroid disease outside the neck (eg, in the mediastinum). (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Missing gland'.)

Identifying parathyroid tissue — Pre- or intraoperative fine needle aspiration of parathyroid tissue for PTH measurement can differentiate parathyroid tissue from other tissues with a high specificity [50,51]. A 25 gauge needle attached to a syringe is used to collect the tissue sample. The aspirated content is diluted with 1 mL of saline solution and centrifuged, and the supernatant is used for PTH measurement with a rapid PTH assay [52]. This technique allows quick tissue identification of parathyroid tissue without frozen section, which can help distinguish an intrathyroidal parathyroid gland from a thyroid nodule or an enlarged lymph node. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'First gland'.)

OUTCOMES — The outcomes of patients who undergo focused parathyroidectomies guided by intraoperative parathyroid hormone (PTH) monitoring support its use by the majority of endocrine surgeons.

Because imaging commonly misses multiple gland disease, most high-volume endocrine surgeons with complex practices use intraoperative PTH to guide not only focused parathyroidectomy but bilateral neck explorations as well [53].

●For patients with sporadic primary hyperparathyroidism, parathyroid exploration guided by intraoperative PTH monitoring is successful in >97 percent of cases, with less extensive surgical dissection, shorter operative times, and smaller incisions than bilateral neck exploration [5-8,32,36].

Although some specialists can perform a bilateral neck exploration with small incisions and as an outpatient procedure, it often leads to a more extensive dissection and excision of additional "enlarged" glands that are assumed to be hyperfunctioning [34,54-60]. However, gland size or weight does not always correlate with parathyroid function [61]. Compared with bilateral neck exploration, a focused parathyroidectomy guided by intraoperative PTH monitoring is not clearly associated with a higher recurrence rate [62,63]. However, the follow-up in these studies is limited [7,11,12,31,64-66].

●Focused operations using intraoperative PTH monitoring are often outpatient procedures. Compared with bilateral neck explorations that often require admission [53], focused operations can lead to a 50 percent decrease in hospital costs and patient charges, despite an increase in laboratory costs [59,67]. However, the costs are not different if bilateral neck exploration can be performed as an outpatient procedure as well [68].

●For patients with equivocal or negative preoperative localization studies [69] and those requiring reoperation [26,70,71], intraoperative PTH monitoring improves the operative success rate, allowing successful unilateral neck exploration in more than 80 percent of such patients.

●The incidence of multiglandular disease in patients with sporadic hyperparathyroidism ranges from 5 to 30 percent [72,73]. The use of the >50 percent PTH drop criterion results in multigland resections in 3 to 10 percent of patients with an operative success rate of 97 to 98 percent [30,38,62,74-77]. The rates of multiple gland resection are higher when the dual criteria are used or when a bilateral neck exploration is performed [18,31,33,56,68,78-80]. (See 'Commonly used protocols' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parathyroid surgery".)

SUMMARY AND RECOMMENDATIONS

●Intraoperative parathyroid hormone (PTH) monitoring allows a more focused, less invasive approach to parathyroidectomy and signals the need for more exploration when PTH drop criterion is not met. Monitoring changes in PTH levels during surgery for sporadic primary hyperparathyroidism provides a useful tool to indicate when all hyperfunctioning parathyroid tissue has been adequately excised and accurately predicts postoperative normal or low calcium levels. (See 'Introduction' above.)

●Intraoperative PTH monitoring takes advantage of the short plasma half-life (three to five minutes) of PTH by using a rapid assay technique that allows measurements while the patient is still in the operating room. (See 'Intraoperative PTH assay' above.)

●At each facility, surgeons should consistently use a protocol that is practical, specific, and reproducible under their local conditions, with the goal of curing 97 to 99 percent of patients of hyperparathyroidism. Two protocols are commonly used. (See 'Intraoperative PTH monitoring protocols' above.)

•The >50 percent PTH drop criterion typically uses four intraoperative PTH samples (pre-skin-incision, pre-gland-excision, 5 minutes post-gland-excision, 10 minutes post-gland-excision). Surgery is concluded when there is a decrease in PTH values of >50 percent from the higher level of either the pre-skin-incision level or pre-gland-excision level.

•The dual criteria require a minimum of two intraoperative samples (a pre-skin-incision level and another one at 10 minutes post-gland-excision). Surgery is concluded when the second PTH level decreases >50 percent compared with the first sample and has returned to the normal range.

The >50 percent PTH drop and dual criteria are intended for patients who have sporadic, primary hyperparathyroidism. They do not necessarily apply to patients with renal or hereditary hyperparathyroidism.

●Rapid PTH assays can also be used to lateralize hyperfunctioning parathyroid glands pre- and intraoperatively, identify missing parathyroid glands, or confirm the presence of parathyroid tissue. (See 'Other uses of rapid PTH assays' above.)

●Intraoperative PTH monitoring allows some patients to undergo a focused parathyroidectomy with less time, less dissection, possibly lower cost and smaller incision, and equal success rate, compared with a bilateral neck exploration, but is also used for bilateral neck explorations by high-volume endocrine surgeons with complex practices. (See 'Outcomes' above.)